The present invention relates to a tetrazolylphenyl pivalate derivative represented by the following general formula (1) or a non-toxic or acid-addition salt of the derivative; and a medicinal composition containing the same as an effective component such as an elastase-inhibitory composition, a medicinal composition for preventing and treating emphysema and a medicinal composition for preventing and treating endotoxin-induced lung disorders: ##STR2##
The human leukocyte elastase is a serine protease present in the azurophil granule of the human polymorphonuclear leukocyte and involved in intracellular decomposition of bacteria and foreign proteins after the phagocytosis.
The human leukocyte-derived elastase degrades not only elastin but also various kinds of constitutive proteins including collagen [Biochemical Journal, 1976, 155, p. 265]. The effect of the elastase, in its normal state, is inactivated by the action of .alpha..sub.1 -protease inhibitor and .alpha..sub.2 -macroglobulin [Annual Review of Biochemistry, 1983, 52, p. 655].
The inhibitory factors are inactivated or damaged under pathological conditions such as cystic fibrosis [Journal of Respiratory Diseases, 1984, 65, pp. 114-124], emphysema [American Review of Respiratory, 1985, 132, pp. 417-433], acute endogastritis [Bulletin of Toho Medical Society, 1992, 38, No. 6, p. 1001]and chronic arthrorheumatism [Journal of Clinical and Experimental Medicine, 1992, 161, No. 9, p. 597]and this results in an unbalance between the enzyme and the inhibitory factors therefor. This in turn leads to degradation of constitutive proteins such as elastin, collagen and proteoglycan and hence a symptom of histoclasis appears. For this reason, the relation between elastase and these diseases has attracted special interest recently and the elastase-inhibitory agent has been expected as an agent for treating and preventing these diseases.
Under the circumstances discussed above, many attempts have recently been done for studying and developing elastase-inhibitory agents and various elastase-inhibitory agents have been proposed and many patent applications concerning the same were filed.
Elastase-inhibitory agents, in particular, pivalate derivatives are disclosed in, for instance, U.S. Pat. No. 4,683,241, The Journal of Pharmacology and Experimental Therapeutics, 1992, 260, pp. 809-815 and Japanese Un-examined Patent Publication (hereunder referred to as "J.P. KOKAI") No. Hei 3-20253.